We propose to study the immunologic and pharmacologic consequences of tumor cell heterogeneity in two dimensions: time and space. Heterogeneity as a function of time refers to the capacity of tumors to undergo progressive, qualitative and quantitative changes over the course of disease. We propose to study how tumor immunogenicity, drug sensitivity and therapeutic strategy change with clinical stage and with the several different, independently assortable characteristics (i.e., latency, growth rate, invasiveness, metastasis) which contribute to malignancy. Heterogeneity as a function of space refers to the marked degree of heterogeneity between individual populations of cells found in a single tumor at a single time. We are establishing a series of cloned cell lines--all tumorigenic--which are derived from a single tumor and which differ markedly in their basic growth properties and karyotype. We propose to compare these lines for the clinical parameters of malignancy, for drug sensitivity and for immunogenicity to see how these also differ within the space of an individual tumor, to study how the different populations interact with each other, and to develop model systems for assessing the optimal therapeutic strategies for dealing with this heterogeneity. Our studies will be performed with spontaneously arising mammary tumors of MMTV-infected strain Balb/cfC3H mice.